VESSELS OF THE BRAIN IN AGING AND ALZHEIMER'S DISEASE

这项提议的目标是研究基本的细胞 衰老和痴呆症的脑循环生物学 确定脑部微循环异常是否 与阿尔茨海默病的发病机制有关。大脑是 一种挑剔的器官，需要大量不间断的 为充足的氧气和代谢提供血液供应 基材，以及处理不需要的产品。另外， 脑毛细血管内皮细胞站在界面上 体循环和神经组织之间的关系 在维持神经元稳定环境中的重要作用 功能和防止潜在毒素进入 大脑。为了做到这一点，大脑的毛细血管内皮细胞 具有独特的特征的，如紧密的细胞间 连接，运输必要的水溶性分子，如 如葡萄糖和酶系统，可以有效地防止 一些脂溶毒素从血液进入大脑。这个 拟议的实验将使用免费的生化和 研究离体脑微血管的药理学技术 从受试者的尸检中获得的人脑皮质组织 无论有没有阿尔茨海默氏症，以及来自Fischer-344大鼠的 三个年龄段。这些实验将解决以下问题 兴趣：(1)人和大鼠的α和β肾上腺素能受体 微血管。(2)利用哇巴因特异性结合的Na+，K+-ATPase 方法：研究方法。(3)葡萄糖转运蛋白在脑中的地位 慢性阻塞性肺疾病患者脑微血管和局部脑膜的研究 阿尔茨海默氏症。(4)酶的作用研究 血脑屏障的“生化”方面。(5)调查 对已知功能蛋白质部分的影响，如转铁蛋白 从血液输送到大脑。 更好地了解大脑循环及其变化 功能可能是欣赏 循环的病理生理学。拟议的研究可能 为进一步认识其发病机制提供科学依据 阿尔茨海默病和衰老中的神经功能障碍。

The goal of this proposal is to investigate the basic cellular biology of the brain circulation in aging and dementia and to determine whether abnormalities of the brain microcirculation are related to the pathogeneis in Alzheimer's Disease. The brain is a fastidious organ that requires a large volume of uninterrupted blood supply for adequate delivery of oxygen and metabolic substrates, and for disposal of unwanted products. Also, the endothelial cells of brain capillaries stand at the interface between the systemic circulation and nervous tissue and have a vital role in maintaining a stable environment for neuronal function and preventing the entry of potential toxins into the brain. To accomplish this, the brain capillary endothelium is endowed with unique features, such as tight intercellular junctions, transporters for essential water-soluble molecules such as glucose, and enzyme systems that can effectively prevent the entry of some lipid-soluble toxins from blood to brain. The proposed experiments will employ complimentary biochemical and pharmacological techniques to study isolated brain microvessels from human cerebral cortical tissue obtained autopsy from subjects with or without Alzheimer's dementia, and from Fischer-344 rats of three age groups. The experiments will address the following interests: (1) alpha and beta-adrenoceptors in human and rat microvessels. (2) Na+, K+ATPase using specific ouabain binding methods. (3) The status of the glucose transporter in brain microvessels and regional brain membranes of subjects with Alzheimer's dementia. (4) Studies of the enzymes that contribute to the "biochemical" aspects of the BBB. (5) Investigation of effects on known functional protein moieties, such as transferrin that are transported from blood to brain. Better understanding of the brain circulation and its altered functions may be a prerequisite for appreciating the pathophysiology of the circulation. The proposed research may provide scientific bases for understanding the pathogenesis of neurological dysfunction in Alzheimer's Disease and aging.